Certain epoxy compounds for insect control

ABSTRACT

Ethers of open chain terpenoid compounds and their monoepoxides were synthesized and found to mimic the juvenile hormones of insects and to be extremely effective as insect control agents.

United States Patent Bowers 1 Oct. 21, 1975 CERTAIN EPOXY COMPOUNDS FOR [56] References Cited INSECT CONTROL UNITED STATES PATENTS [75] Inventor: William S. Bowers, Geneva, NY. 3,655,700 4/1972 Siddall 260/3405 3,681,385 8/1972 Siddall 424/278 1 Asslgfleei The tt e iiitatttfi 0; 151112103 2: 3,825,661 7 1974 Emmick 424/278 represen y e ecre ry 0 Agriculture, Washington, DC. OTHER PUBLICATIONS Borkovec, A., Insect Chemosterilants, Vol. VII,

[2l] Appl. No.: 499,809

Primary ExaminerV. D. Turner Related Apphcanon Data Attorney, Agent, or Firm-M. Howard Silverstein; Max [62] Division of Ser. No. 363,295, May 23, 1973, Pat. No. D H n l y; W E, S ott 3,852,472, which is a division of Ser. No. 78,577, OCt. 6, 1970, abandoned. 52 US. Cl 424/278; 424/010. 12 9 chain terpenfid compm'lds and 2 monoepoxldes were synthes1zed andfound to m1m1c [51] Int. Cl. A01N 9/28 h h d b l 58 Field of Search 424/278, DIG. 12, 282; t e Juveme 0 to e extreme) effective as insect control agents.

1 Claim, N0 Drawings CERTAIN EPOXY COMPOUNDS FOR INSECT CONTROL This application is a division of applicationSer. No. 363,295, filed May 23, 1973, now US. Pat. 3,852,472, which is in turn a division of application Ser. No. 78,577, filed Oct. 6, 1970, now abandoned.

This invention relates to insect control and more particularly to compounds and to the preparation of compounds that have high juvenile hormone activity and which are highly ovicidal to insect eggs.

There is considerable concern throughout the world about the persistence of many insecticides and insecticide residues in our environment and the potential hazard that these materials represent to human populations. In addition, many species of insect pests have become resistant or immune to many of the insecticides on the market. Thus, more selective chemicals are required which will not pose a threat to human populations and to which the insects will not develop resistance.

The compounds of the present invention should be suitable replacements for the insecticides now being used to control stored product insects and many social pests such as fireants and termites. In addition, it may be feasible to use these compounds in field applications to control a wide variety of insects, the toxicity of the compounds to vertebrates should be insignificant, and the cost to produce them commercially should be very competitive with that of well known insecticides.

One object of this invention is to provide a means for achieving selective, safe, economical control of insect pests.

Another object is to provide chemical compounds that prevent insect maturation when applied topically, when fed to insects or when applied in a vapor state as a fumigant, to an insect in an immature stage of growth.

A further object of this invention is to provide compounds that adversely affect the biological function of insects, particularly their ability to mature to an adult stage.

In general, according to the present invention the terpenoid ethers and their corresponding epoxides are synthesized and found to prevent insect maturation when applied to immature stages of several species of insects by topical application, by feeding or by fumigation (exposure to vapor). Thus an immature insect exposed to these compounds is unable to metamorphose into a normal adult. Topical application of as little as 10.0 nanograms (0.01 ,ug) of the more active compounds in this series is sufficient to prevent metamorphosis. The insect which emerges from the treated pupa retains immature genitalia which preclude copulation and reproduction. The insects die shortly after molting to this adultoid condition. Also, when used as a vapor or as a dip treatment for eggs the compounds drastically reduce egg hatch.

The compounds of this invention having the following general formula.

wherein Y is R is a straight chain alkyl containing from 1-2 carbon atoms such as CH CH CH x is a number from 1 to 2, and

Z is one of the following groups:

CH CH O(CH ),,CH in which n is 0-3;

CH COO(CH ),,CH in which n is O-l;

and

in which n is 0-3.

The terpenoid portions of the compounds were prepared in part by the Marc Julia synthesis [Bull Soc. Chem. France 1072, (1960)] as outlined below.

Oxidation was performed with chromic acid solution in acetone [1. Chem. Soc. 2548( 1953)] The vinyl alcohols are prepared by the grignard reaction with vinyl magnesium bromide (or chloride) in tetrahydrofuran.

The vinyl alcohols were converted to the allylic bromides by treatment with hydrogen bromide in aqueous or acetic acid solution. Thus, an aliquot of the vinyl alcohol was added dropwise to a rapidly stirred ice cold aqueous or acetic acid solution containing 2 molar equivalents of hydrogen bromide. When addition was complete, stirring was continued for minutes and then the reaction mixture was poured into an excess of ice cold 5% sodium carbonate solution, extracted with diethyl ether and washed to neutrality with water. After drying the ethereal extracts over sodium sulfate and removal of the solvent in vacuo, the allylic bromides were obtained in nearly quantitative yield.

CH CH in which n is O to 3;

were synthesized by coupling the foregoing bromides with the respective alcohols of A to form the corresponding ethers by refluxing the bromides or stirring at room temperature for several hours with a slight molar excess of the alcohols and a base such as powdered potassium hydroxide or potassium teritary butoxide in an anhydrous solvent such as diethyl ether, dimethoxyethane or dimethyl formamide. Alternatively, the reactants were sealed in a small reaction bomb and place in an oven at 150C for 2-4 hours.

The reaction mixture was then diluted with water and extracted several times with hexane. The hexane extracts were combined and washed to neutrality with water The hexane portion was dried over sodium sulfate and the solvent removed in vacuo to yield the crude ethers.

Another series of compounds in which the terpenoid The crude ethers obtained from the foregoing reactions carbon chain was one carbon longer were prepared in a similar manner except that the bromides were prepared by a continuation of the Julia synthesis as follows:

were purified by chromatography over florisil. The crude material was put on a florisil column (30 gm florisil/gm crude material) in hexane and eluted stepwise with increasing concentrations of diethyl ether in hexane. Purity was determined by gas-liquid chromatography and infra-red spectroscopy to be greater than 99%.

Compounds of the general formula wherein Y is CH CH R is a straight chain alkyl containg from l-2 carbon atoms such as CH CH CH x is a number from 1 to 2; and

E is CH COO(CH ),,CH

in which n is O to l were prepared from the terpenoid alcohols. The allylic terpenoid alcohols were prepared from their corresponding vinyl analogs by chromic acid oxidation [J Chem. Soc. 2548 (1953)] to the conjugated aldehyde, followed by reduction to the primary alcohol with a metal hydride such as sodium borohydride in methanol, or lithium aluminum hydride in ether.

The primary halides of E, (Br CH COO(CH CH or Br CH CH CH were coupled with the terpenoid alcohols under basic conditions in a reaction bomb, under reflux, or by stirring at room temperature for an extended period of time.

R CH R CH3 CH2 The reaction was complete in 1 hour and the reaction mixture was extracted with diethyl ether and washed successively with 5% aqueous sodium carbonate and water. The ethereal extract was dried over anhydrous sodium sulfate. The crude product was isolated by evaporation of the solvent in vacuo.

The desired compounds were purified by column chromatography over florisil as previously described.

Purity was determined by gas-lipid chromatography base The crude ethers were purified by chromatography The epoxides were purified by chromatography over v the general structure.

wherein Y is R=Straight chain alkyl containing from l-2 carbon atoms such as CH CH CH x is a number from 1 to 2; and

n is a number from O to 3 were prepared by stirring the terpenoid alcohols for 2 hours at room temperature with the appropriate vinyl 65 hexane removed in vacuo. 13.6 g. of crude compound ether in the presence of a catalytic amount of hydrochloric acid.

florisil as previously described.

Purity was ascertained by gas-liquid chromatography and infrared spectroscopy to be greater than 99%.

The compounds and their epoxides prepared by the above procedures are shown in Table l.

Although the general procedures just described are undoubtedly adequate for those skilled in the art, the following examples further illustrate the preparation of compounds within the scope of each of the general structures shown above.

Synthesis of Compound 49 in Table I In a 500 ml. boiling flask, 10.8 g. ethylene glycol butyl ether, was combined with 10.2 g. potassium tertbutoxide and 10 g. geranyl bromide in 100 ml. dimethoxyethane. The reaction mixture was stirred at room temperature for 16 hrs. and then poured into 200 ml. of hexane and washed 2X with water and 1X with saturated'aqueous sodium chloride solution. The organic layer was dried over anhydrous sodium sulfate and the was recovered and found to be suitable for the subsequent epoxidation.

Epoxidation of Compound 49 in Table l Dissolyod 4 of tho Compound 49 in 50 z z Dissolved 1.3 g. of Compound 65 in 30 ml. CH C1 and and with stirring added 3.2 g. m-chloroperbenzoic acid added in aliquots 1.0 gm. of m-Chloroperbenzoic acid. 1n aliquots. Stirred 30 min. and then made the solution Reaction stirred 30 min. Solution made basic with 10% basic with 10% aqueous sodium carbonate. Stripped off 1 aqueous sodium carbonate. Stripped off solvent in the solvent in vacuo. Residue was dissolved in diethyl vacuo. Residue dissolved in diethyl ether and washed ether and washed in a separatory funnel with soin a separatory funnel with 10% sodium carbonate 2X drum carbonate 2X, and water 2X. Dried organic layer and with water 2X. Dried over anhydrous sodium sulover anhydrous sodium sulfate. Stripped off solvent in fate. Crude epoxide, Compound 73, was 1.3 g. The vacuo. Crude epoxide yield was 3.8 gm. Fractionation crude epoxide was fractionated by column chromatogof the crude epoxide over 60 gm. of florisil by stepwise raphy as specified for Compound 65. Yield of pure epelution with increasing concentrations of diethyl ether oxide, Compound 73, was 950 mg. (Compound 73) Synthesis of Compound 81 in Table I OCH- COOCH M Brcmcoocn x in hexane gave 3.0 g. pure epoxide. (Compound No. Stirred 5 gm geraniol with 3.5 gm. potassium tert 57) butoxide in 50 ml. dimethoxyethane for minutes.

Synthesis of Compound 65 in Table II cinc c II Br HOCH CHCH OCHg H; I

Combined 10 gm. glycerol acetonide and 5.4 gm. po- Added to above 5.8 g. of methyl bromoacetate and tassium tertbutoxide in 50 ml. dimethoxyethane and 40 stirred at room temperature for 16 hrs. Reaction mixstirred for 20 min. Added 8.2 g. geranyl bromide and ture dissolved in 200 ml. diethyl ether and washed in a continued stirring at room temperature for 16 hrs. Filseparatory funnel with water 3X. Organic layer dried tered, stripped off dimethoxyethane, dissolved residue over anhydrous sodium sulfate. Stripped off solvent in in diethyl ether and washed with water in a separatory vacuo. Yield of crude Compound 81 was 7.3 gm.

funnel 3X. Dried organic layer over anhydrous sodium The crude ether was chromatographed on a column sulfate and stripped off solvent in ether. Crude ether containing 150 gm. of florisil. Elution with increasing Compound 65 yield was 6.7 gm. concentrations of diethyl ether in hexane gave a pure fraction containing 1.4 gm. of Compound 81.

Epoxidation of Compound 89 in Table l 3 gm. of Compound 65 was fractionated by column Dissolved 1 gm. of Compound 81 in 25 m1. of CHCl chromatography over 70 gm. of florisil. Stepwise elu- Hexane (3-2) containing 0.4 gm. sodium bicarbonate tiOn with increasing concentrations of diethyl ether in with stirring in an ice bath, To this was added dropwise hexane ga 9 gf p Compound 1.0 gm. m-chloroperbenzoic acid in 25 ml. of CHC1 Epoxidation of Compound in Table II Hexane (3-2). After addition, stirring in the ice bath Geraniol (10 gm.) in ml. diethyl ether was added was maintained for 15 min. Sodium sulfite was added dropwise to 14 g. ethyl vinyl ether containing 1 drop of to destroy any excess peracid. The reaction mixture concentrated HCl. After addition, stirring was mainwas dissolved in about 200 ml. of diethyl ether and tained for 2 hrs. in a warm water bath (ca. 50C.).

washed in a separatory funnel with 10% aqueous so- 5 The reaction mixture was dissolved in 200 ml. of didium carbonate 2X and water 2X. Organic layer was ethyl ether and washed in a separatory funnel with 5% dried over anhydrous sodium sulfate and the solvent aqueous sodium carbonate IX, and water 3X. The orstripped off in vacuo. Yield of crude Compound 89 was ganic layer was dried over anhydrous sodium sulfate.

1.26 gm. The solvent was stripped off in vacuo. The crude acetal 10 yield was 14.5 gm. Filtration of 5 gm. of the acetal in The crude Compound 89 was fractionated over gm. hexane through a column containing 150 gm. of florisil of florisil as specified for Compound 81 and 770 mg. of gave a quantitative return of 5 gm. of pure acetal Compure Compound 89 was obtained. Analysis by gaspound 145. Purity ascertained by gas-chromatography chromatography and infrared. (Compound 89) and infrared analysis.

Synthesis of Compound I 13 in Table l Epoxidation of Compound 145 in Table l Oi a a HOCzHs OCHOC H o Dissolved 5 g. geraniol in 50 ml. dimethoxyethane con- To a stirred solution of 5 gm. of Compound 145 in 100 taining 3.5 g. potassium tert-butoxide with stirring for 30 ml. hexane was added dropwise 4.94 gm. m- 30 min. Added 4.4 g. epibromohydrin and stirred at chloroperbenzoic acid dissolved in 100 ml. CH Cl room temperature for 3 hrs. Filtered, dissolved in about After addition, stirring was continued for 20 min. Ex- 250 ml. diethyl ether and washed with water 3X in a cess peracid was destroyed with sodium sulfite. The reseparatory funnel. The organic layer was dried over anaction mixture was made basic with 5% aqueous potashydrous sodium sulfate and the solvent stripped off in sium hydroxide and the solvent stripped off in vacuo. vacuo. Yield of crude ether was 7.6 gm. The crude The residue was dissolved in diethyl ether and washed ether was fractionated by column chromatography in a separatory funnel with 5% aqueous potassium hyover 150 gm. of florisil. Stepwise elution with increasdroxide IX and with water 3X.

ing concentrations of ether in hexane gave 2.24 gm. of Organic layer was dried over anhydrous sodium sulfate pure Compound 113. and the solvent stripped off in vacuo. Yield of crude Epoxidation of Compound 1 13 in Table I o o Wocmcucn. HQ Z Dissolved 2.24 g. of Compound 113 in ml. CH Cl Compound 153 was 5.0 gm. and with stirring added 2.2 g. m-chloroperbenzoic acid 59 Fractionization of 5.0 gm. of Compound 153 by colin aliquots. Stirred an additional 30 min., made basic umn chromatography over 100 gm. of florisil by stepwith 10% aqueous sodium carbonate, dissolved in 200 wise elution with increasing concentrations of diethyl ml. diethyl ether and washed with 10% aqueous sodium ether in hexane gave 3.0 gm. of pure Compound 153. carbonate 2X and with water 2X in a separatory funnel. Analysis by gas-chromatography and infrared. (Com- Organic layer dried over anhydrous sodium sulfate. Pound Yield of crude Compound 121 was 2.0 gm. Column The m ph gen ic e fects of some of the comhromat g h f C d 121 over fl i il pounds in the Tenebrio genitalia assay (Life Sciences by stepwise elution with increasing concentrations of 1965) are Shown in Table II.

di h l ether i hexane gave 713 f pure C Topical application to Tenebrio pupae of as little as pound 121. Analysis by gas-chromatography and infral0 a g Mg) of Several COmPOUHdS red. (Compound 121) 26, 28, 57, 73) resulted in the retention of complete Synthesis of Compound in Table l CH pupal genitalia after the ultimate molt toward the adult beetle. Topical application of 100 nanograms (O.l pg) resulted in the development of pupal-adult intermediates.

Topical application of somewhat greater amounts of 57, 73, 81, 89, 153, on the Mexican bean beetle. Topical application of nanogram to microgram quantities of these compounds prevents normal adult development and the insects die during the ultimate molt. Topical 5 treatment of Mexican bean beetle eggs with extremely unds 76, 89, 121, 153, were requ re Induce dilute acetone solutions of these compounds caused seretention of pupal genitalia and/or produce pupal-adult Vere reduction in egg hatch intermediates in Tenebrio. In all cases the affected in- Table Iv shows the morphogenetic effects of sects were unable to form normal adults and died durpounds 257 26 28, 57 73 89, 121, 153 on Tenebrio ing or shortly aftertheir ultimate molt without signifi- 10 after exposure of the pupae to the vapors of these Cam feedmg and any reproducuon pounds. These results exemplify the potential use of the Table III shows the effects of compounds 25, 26, 28, Compounds as fumigams- TABLE I Synthesized Terpenoid Ethers and Their Epoxides l W O--Cl-l,CH,-O-CH 2 M OCH2CH,-O-CH;,

3 W- OCH2CH2O-CH;

4 M- O- CH,CH2-OCH3 5 o cH,cH, o cH M 6 0--CH,Cl-l 0-CH W 7 0 CH,CH,0-CH

8 W O-CH,CH -OCH,

9 W- 0 Cl-l CI- -0-CH 10 OCH2CH1OCH;

11 W 0 CH2CH2OCH3 o 12 W O CH2CH2OCH3 3,914,429 13 U TABLE 1-Continued Synthesized Terpenoid Ethers and Thir E iox ides Synthesized Terpenoid Ethers and Their Epoxides TABLE I-Continued Synthesized Terpenoid Ether: and Their Epoxides OCH CH 0(C z)a a TAB LE IContinued Synthesized Terpenoid Ethers and Their Epoxides v 3,914,;4 2'9 21 22 TABLE lContinued r v Synthesized Terpenoid Ethers and Their Epox ides CH CH3 CH CH CH CH;

CI-{Cil TAB LE I Continued Synthesized Terpenoid Ethels and Th eir Epoxides OCH:

\ ocH OCH3 OCH,

OCH -OCH lap-0cm OCH, OCH;;

O OCH,HOCH

o OCHJ'L-OCH;

OCH, OCH;,

OCl-hE-OCH;

TABLE I-Continu Synthesized Terpenoid Ethel-s and Their Epoxides TABLE I-Continued I Synthesized Terpenoid Ethers and Their Epoxides 3 129 AWOiH-OCH;

131 MDv-OiH-OCH;

132 WH-OCH;

133 Wolpocn 134 MEL-OCH,

136 Wain-0cm 137 AM-OJIH-OCR,

139 W- HOCH:

140 H-OCH;

TABLE I C0ntinued Synthesized Terpenoid Ethers and Their Epoxides Mix:

H-OCH o H-OCH;

H-OCH O TAB LE 1 Continued Synthesized Terpenoid Ethers and Their Epoxides HOCH CH H-OCH CH H-OCH CH CH HOCH CH CH TA B LE l- Continued Synthesized Terpenoid Ethers and Their Epoxides Oi W- 11 oc1-1,cu.cti

M CH3 l74 OH-OCHgCHgCHg able II Table IV Morphogenetic Effects of Representative Compounds in Morphogentlc Effects of Representative Compounds on the Tenebrio Genitalia Assay Tenebrio pupae by Fumigation. Compound Micrograms of Compound Required to Compound Mlcrograms of Compound Required to Number Produce the Indicated Morphogenetic Effects Product Pupal-Genitalia and Pupali P LAd n Number in Adult intermediates by Vapor Expo- Table l lntennediates Pupal Genitalia 0 Table l sure 25 O l 0.01 25 0.1 5.0 26 0.1 0.01 26 0.1 5.0 28 0.1 0.01 28 Ol 5.0 57 0.1 0.01 57 0.1 5.0 73 0.1 0.01 73 7 0 01 89 0.1 5.0 89 1000 L0 121 1.0 -10.0 121 100.0 1.0 153 1.0-10.0 153 100.0 10.0

'Pupal adult intermediates represent an intermediate in which the insect molts to a monster with an essentially pupal abdomen and an adultoid head and thorax. Pupal genitalia refers to the effect in which the insect is nearly adult but retains immature genitalia.

Each of the above morphogentic effects causes the insect to die shortly thereafter.

Table III Reduction in Adult Emergence and Egg Hatch of Mexican Bean Beetle Epilachna varivestis Compound Micrograms of Compound PPM of Compound Required to cause 90% Required to cause Topical treatment of 2-day old prepupae with an acetone solution of compound. "Topical treatment by dipping egg masses in an acetone solution of compound. An acetone control conducted for each of the above treatments showed that the solvent contributed nothing to the effect of the compounds.

Compounds were spread over the lid of a I00 rm diameter petri dish in a small volume of acetone and after evaporation of the acetone the lid was placed over the bottom of the petri dish containing newly melted Tenebrio pupae. The pupae were therefore exposed only to the vapors and did not come in contact with the compound directly. The insects were lefi in the dish until they underwent the final molt toward the adult.

I claim:

1. A method of preventing the hatching of eggs of the insects Epilachna varivestis comprising applying to said insect eggs an effective egg hatch preventive amount of a compound of the formula:

wherein R and R are straight chain alkyls containing from 1 to 2 carbon atoms; x is a number from 1 to 2; and Z is selected from the group consisting of (CH O(CH ),,CH in which it is a number from 0 to 1;

37 38 in which n is a number from to 1; f u

C H- i \o CHO(CH2)nCH 5 CH2CHCH2 in which n is a number from 0 to 3;

said compound being applied as a solute in acetone. 

1. A METHOD OF PREVENTING THE HATCHING OF EGGS OF THE INSECTS EPILACHANA VARIVESTIS COMPRISING APPLYING TO SAID INSECT EGGS AN EFFECTIVE EGG HATCH PREVENTIVE AMOUNT OF A COMPOUND OF THE FORMULA: 